Many children with sickle cell disease (SCD) who have no history of overt stroke are still at risk for brain injury manifested by cognitive impairment, a major source of morbidity in this population. Unfortunately, conventional diagnostic methods, such as anatomical MRI, MRA and TCD are not sensitive for demonstrating the extent and severity of brain injury, and may be normal in the majority of those children. Thus there is a need for more sensitive diagnostic tools that can identify children at risk before onset of brain injury. In a subset of children with cognitive impairment, anatomical MRI may demonstrate silent infarctions, the pathogenesis of which is complex and remains speculative. Importantly, several studies have shown associations between extent of silent infarctions and severity of cognitive impairment. However, reports on associations between location of silent infarcts and type of cognitive dysfunction are less convincing and sometimes inconsistent. Possible reasons may be related to 1) use of anatomical MRI as the only surrogate marker for brain injury, 2) qualitative assignment of total lesion burden and spatial distribution in the brain, and 3) lack of longitudinal comparison of subjects. To address those issues we intend to 1) use advanced MRI-based techniques (perfusion and quantitative MRI for measuring T1-relaxation of brain parenchyma) specially designed to interrogate the microcirculation and microstructure of the brain in order to gain further insight into the pathogenesis of brain injury, 2) demonstrate that those advanced MRI-based techniques are sensitive predictors of subsequent increase in the volume of silent infarctions, and progressive decline in performance on neuropsychological tests, and 3) integrate cross sectional and longitudinal data into our computer-based Brain-Image Database (BRAID) so that we can more accurately quantify and map regional MRI-based abnormalities and better correlate with type of cognitive dysfunction. The results of this project will help identify risk factors for silent brain infarcts and cognitive decline in children with SCD, provide some insight into the pathogenesis of these silent infarcts, and improve our understanding of the relationship between the spatial distribution of MRI-based brain abnormalities and domain-specific brain dysfunction measured by tailored neuropsychological tests.